Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcoma (KS) tumors, pleural effusion lymphomas, and multicentric Castleman's diseases. While there is a reduction in the incidence of KS among patients receiving HAART, an increasing concern is the development and spread of drug resistant HIV-1 strains, which in turn leads to reoccurrence of KSHV-associated malignancy. Despite being this pressing human health problem, however, very little has been done thus far to study host's immune responses and potential vaccine development against KSHV infection and its associated diseases. This is primarily because of the lack of proper genetic system and animal model that support in vivo studies on KSHV replication, persistence, and pathogenesis. We have recently established a new infectious bacterial artificial clone of KSHV genome (BAC16) that significantly improved the efficiency of the genetic manipulation and virus production system. Besides this, we have also established the first successful zoonotic or cross-species transmission of KSHV into non-human primates, common marmosets (Callithrix jacchus). Our specific preliminary results are: (1) the KSHV BAC16 is stable and produce infectious virus (~106-7 titers); (2) common marmosets intravenously or orally inoculated with recombinant KSHV rapidly sero-converted and maintained a high anti-KSHV antibody response over a long period of time; and (3) remarkably, orally infected marmoset developed KS-like skin lesions with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These genetic and animal models significantly recapitulate the important aspects of KSHV infection in humans, thus providing a unique opportunity in developing potential vaccine strategies against KSHV infection. Thus, recombinant viruses will be constructed to determine their roles in viral infection in cultures, mice, and primates, and ultimately establish the foundations for the rationale design of vaccine candidates. Thus, the goal of this study is two-fold: firstly, to develop genetically modified KSHV strains to be used as vaccine candidates and secondly, to further build up the animal models of KSHV infection for vaccine development. This proposal is highly innovative and a successful outcome should prove to be a major discovery that significantly impacts the understanding of KSHV infection to ultimately reveal novel protective and/or therapeutic vaccine strategies.